High Viscosity Liquid Controlled Delivery System and Medical or Surgical Device

ABSTRACT

The present invention relates to novel nonpolymeric compounds and compositions that form liquid high viscosity materials suitable for the delivery of biologically active substances in a controlled fashion, and for use as medical or surgical devices. The materials can optionally be diluted with a solvent to form a material of lower viscosity, rendering the material easy to administer. This solvent may be water insoluble or water soluble, where the water soluble solvent rapidly diffuses or migrates away from the material in vivo, leaving a higher viscosity liquid material.

This application is a continuation of U.S. application Ser. No.11/888,621, filed Jul. 31, 2007, which application is continuation ofU.S. application Ser. No. 10/316,441, filed Dec. 10, 2002, now U.S. Pat.No. 7,833,543, which application is a continuation-in-part of U.S.application Ser. No. 09/699,002, filed Oct. 26, 2000, now U.S. Pat. No.7,053,209, which application is a divisional of U.S. application Ser.No. 09/385,107, filed Aug. 27, 1999, now U.S. Pat. No. 6,413,536, theentire contents of each of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel nonpolymeric compounds andcompositions that form liquid, high viscosity materials suitable for thedelivery of biologically active substances in a controlled fashion, andfor use as medical or surgical devices. The materials can optionally bediluted with a solvent to form a material of lower viscosity, renderingthe material easy to administer. This solvent may be water insoluble orwater soluble, where the water soluble solvent rapidly diffuses ormigrates away from the material in vivo, leaving a higher viscosityliquid material.

2. Description of Related Art

There has been extensive research in the area of biodegradablecontrolled release systems for bioactive compounds. Biodegradablematrices for drug delivery are useful because they obviate the need toremove the drug-depleted device.

The most common matrix materials for drug delivery are polymers. Thefield of biodegradable polymers has developed rapidly since thesynthesis and biodegradability of polylactic acid was reported byKulkarni et al., in 1966 (“Polylactic acid for surgical implants,” Arch.Surg., 93:839). Examples of other polymers which have been reported asuseful as a matrix material for delivery devices include polyanhydrides,polyesters such as polyglycolides and polylactide-co-glycolides,polyamino acids such as polylysine, polymers and copolymers ofpolyethylene oxide, acrylic terminated polyethylene oxide, polyamides,polyurethanes, polyorthoesters, polyacrylonitriles, andpolyphosphazenes. See, for example, U.S. Pat. Nos. 4,891,225 and4,906,474 to Langer (polyanhydrides), 4,767,628 to Hutchinson(polylactide, polylactide-co-glycolide acid), 4,530,840 to Tice, et al.(polylactide, polyglycolide, and copolymers), and 5,234,520 (Dunn etal., biodegradable polymers for controlled delivery in treatingperiodontal disease).

Degradable materials of biological origin are well known including, forexample, crosslinked gelatin. Hyaluronic acid has been crosslinked andused a degradable swelling polymer for biomedical applications (U.S.Pat. No. 4,957,744 to Della Valle et al.; (1991) “Surface modificationof polymeric biomaterials for reduced thrombogenicity,” Polym. Mater.Sci. Eng., 62: 731-735]).

Biodegradable hydrogels have also been developed for use in controlleddrug delivery as carriers of biologically active materials such ashormones, enzymes, antibiotics, antineoplastic agents, and cellsuspensions. Temporary preservation of functional properties of acarried species, as well as the controlled release of the species intolocal tissues or systemic circulation, have been achieved. See forexample, U.S. Pat. No. 5,149,543 to Cohen. Proper choice of hydrogelmacromers can produce membranes with a range of permeability, pore sizesand degradation rates suitable for a variety of applications in surgery,medical diagnosis and treatment.

Many dispersion systems are currently in use as, or being explored foruse as, carriers of substances, particularly biologically activecompounds. Dispersion systems used for pharmaceutical and cosmeticformulations can be categorized as either suspensions or emulsions.Suspensions are defined as solid particles ranging in size from a fewnanometers up to hundreds of microns, dispersed in a liquid medium usingsuspending agents. Solid particles include microspheres, microcapsules,and nanospheres. Emulsions are defined as dispersions of one liquid inanother, stabilized by an interfacial film of emulsifiers such asurfactants and lipids. Emulsion formulations include water in oil andoil in water emulsions, multiple emulsions, microemulsions,microdroplets, and liposomes. Microdroplets are unilamellar phospholipidvesicles that consist of a spherical lipid layer with an oil phaseinside, as defined in U.S. Pat. Nos. 4,622,219 and 4,725,442 issued toHaynes. Liposomes are phospholipid vesicles prepared by mixingwater-insoluble polar lipids with an aqueous solution. The unfavorableentropy caused by mixing the insoluble lipid in the water produces ahighly ordered assembly of concentric closed membranes of phospholipidwith entrapped aqueous solution.

U.S. Pat. No. 4,938,763 to Dunn, et al., discloses a method for formingan implant in situ by dissolving a non-reactive, water insolublethermoplastic polymer in a biocompatible, water soluble solvent to forma liquid, placing the liquid within the body, and allowing the solventto dissipate to produce a solid implant. The polymer solution can beplaced in the body via syringe. The implant can assume the shape of itssurrounding cavity. In an alt native embodiment, the implant is formedfrom reactive, liquid oligomeric polymers which contain no solvent andwhich cure in place to form solids, usually with the addition of acuring catalyst.

While a number of materials have been evaluated for use in thecontrolled delivery of substances, there remains a need to provide moresimple systems with low toxicity for the controlled delivery ofsubstances. The delivery systems described above, for example, requirethe preparation of polymers and loaded polymeric matrices, or hydrogels,or other complex or fragile compositions. In particular, there is a needto provide a liquid-based delivery system that is easily formulated witha substance to be delivered and easily administered.

Therefore, it is an object of the invention to provide a simple systemfor the delivery of substances.

It is another object of the invention to provide a liquid-based deliverysystem that is easily formulated with a substance to be delivered andeasily administered.

It is another object of the present invention to provide a method forthe controlled delivery of substances in a simple liquid-based system.

SUMMARY OF THE INVENTION

The invention relates to compounds, and to compositions containing them,as well as to methods of using these compounds and compositions asdelivery vehicles, for example as controlled delivery vehicles, forsubstances, such as bioactive substances. The invention also relates tothese compounds, compositions, and methods of using them as medical orsurgical devices, such as medical or surgical implants, films, or graft,compositions. The compositions are generally in liquid form, and containat least one non-water soluble, high viscosity, liquid carrier material.

In one aspect, the invention relates to a liquid composition for thedelivery of biologically active substances having (a) a non-polymeric,non-water soluble high viscosity liquid carrier material having aviscosity of east at least 5000 cP at 37° C. that does not crystallizeneat under ambient or physiological conditions, and is present in anamount from about 99.5 percent to about 1 percent by weight, moreparticularly from about 95 percent to about 10 percent by weight,relative to the total weight of the composition; and (b) a biologicallyactive substance.

In another aspect, the invention relates to a liquid composition for thedelivery of biologically active substances having (a) a non-polymeric,non-water soluble high viscosity liquid carrier material having aviscosity of at least 5,000 cP at 37° C. that does not crystallize neatunder ambient or physiological conditions; (b) a biologically activesubstance; and (c) a solvent in which the non-polymeric non-watersoluble liquid carrier material is soluble.

In another aspect, the invention relates to a liquid composition for thedelivery of biologically active substances having (a) a non-polymeric,non-water soluble high viscosity liquid carrier material having aviscosity of at least 5,000 cP at 37° C. that does not crystallize neatunder ambient or physiological conditions; (b) a biologically activesubstance; and (c) an additive.

In another aspect, the invention relates to a liquid composition for thedelivery of biologically active substances having (a) a non-polymeric,non-water soluble high viscosity liquid carrier material having aviscosity of at least 5,000 cP at 37° C. that does not crystallize neatunder ambient or physiological conditions; (b) a biologically activesubstance; and (c) a solvent in which the non-polymeric non-watersoluble liquid carrier is soluble, and (d) an additive.

In another aspect, the invention relates to a liquid composition for thedelivery of biologically active substances and suitable for topical,systemic, parenteral, rectal, vaginal, nasal, pericardial, or oraladministration, or a combination thereof, having (a) a non-polymeric,non-water soluble high viscosity liquid carrier material having aviscosity of at least 5,000 cP at 37° C. that does not crystallize neatunder ambient or physiological conditions; and (b) a biologically activesubstance.

In another aspect, the invention relates to a liquid composition for thedelivery of biologically active substances having (a) a non-polymeric,non-water soluble high viscosity liquid carrier material having aviscosity of at least 5,000 cP at 37° C. that does not crystallize neatunder ambient or physiological conditions; (b) a biologically activesubstance; and (e) a lower viscosity liquid carrier material.

In another aspect, the invention relates to a liquid composition for thedelivery of biologically active substances having (a) a non-polymeric,non-water soluble high viscosity liquid carrier material having aviscosity of at least 5,000 cP at 37° C. that does not crystallize neatunder ambient or physiological conditions; and (b) a biologically activesubstance useful for agricultural, human therapy, veterinary, orpesticidal purposes, or a combination thereof.

The carrier material may comprise a nonpolymeric ester or mixed ester ofone or more carboxylic acids. In particular, the carrier material canhave a viscosity of at least 5,000 cP at 37° C. In addition, the carriermaterial may possess the property that it does not crystallize neatunder ambient or physiological conditions.

The compositions can be dissolved in a physiologically acceptablesolvent to lower their viscosity, rendering them easier to administer.After administration of compositions containing water-soluble solvents,however, the solvent diffuses or otherwise dissipates away from thematerial, which thus increases significantly in viscosity, and therebyforms a controlled release matrix for a bioactive substance, orbioactive substance, or a medical or surgical implant, film, or graft.Non-water soluble solvents may also be used, but will diffuse away fromthe nonpolymeric ester or mixed ester much more slowly.

Dissolution in solvent is particularly useful with nonpolymeric estersor mixed esters having very high viscosities, e.g., on the order of100,000 cP at 37 C. Some nonpolymeric esters or mixed esters suitablefor use in the invention, while having viscosities above 5,000 cP at 37°C., are not as viscous, and may be administered neat, i.e., without theaddition of a solvent.

In another aspect, the invention relates to a method of administering abiologically active substance to a plant or an animal (including humans)by administering to the plant or animal a composition containing anon-water soluble, high viscosity, liquid carrier material comprising anonpolymeric ester or mixed ester of one or more carboxylic acids,having a viscosity of at least 5,000 cP at 37° C., that does notcrystallize neat under ambient or physiological conditions and abiologically active substance. The particular method of administrationmay vary, and may include topical, oral (e.g., as a solution, emulsion,or in a gelatin capsule), nasal, pulmonary, rectal, vaginal, orinjectable routes for animals, and topical or injectable routes forplants.

In another aspect, the invention relates to a medical or surgicalimplant, film, or graft composition containing a non-water soluble, highviscosity, liquid carrier material comprising a nonpolymeric ester ormixed ester of one or more carboxylic acids, having a viscosity of atleast 5,000 cP at 37° C., that does not crystallize neat under ambientor physiological conditions.

In yet another aspect, the invention relates to a method for the in vivoformation of an implant, film, or graft in a patient in need thereof,including:

(1) contacting with the tissue of the patient a mixture containing:

-   -   (a) a non-water soluble, high viscosity, liquid carrier material        comprising a nonpolymeric ester or mixed ester of one or more        carboxylic acids, having a viscosity of at least 5,000 cP at 37°        C., that does not crystallize neat under ambient or        physiological conditions; and    -   (b) a solvent in which the non-polymeric, non-water soluble        liquid carrier material is soluble;        wherein the mixture has a viscosity of less than the viscosity        of the high viscosity liquid carrier material; and

(2) allowing the solvent to dissipate or diffuse into the tissue of thepatient, thereby forming an implant, film or graft of the non-polymeric,non-water soluble, high viscosity liquid carrier material. In an evenmore particular aspect of the invention, the mixture has a viscosity ofless than approximately 6,000 cP, more particularly less thanapproximately 4,000 cP, even more particularly, less than approximately1,000 cP, at 37° C.

In yet another aspect, the invention relates to novel compounds having astructure selected from the group consisting of:

wherein R¹, R², and R³ are independently selected from the groupconsisting of hydrogen, alkanoyl having 2 to 6 carbons,hydroxy-substituted alkanoyl having 2 to 6 carbons, andacyloxy-substituted alkanoyl having 2 to 6 carbons, wherein n is between1 and 20, and wherein at least one of R¹, R², and R³ is other thanhydrogen;

R¹—O—(CH₂)_(n)—O—R²  III:

wherein n is a integer between 4 and 8, and R¹ and R² are independentlyselected from the group consisting of hydrogen, alkanoyl having 2 to 6carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, andacyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at leastone of R¹ and R² is other than hydrogen;

wherein R¹, R², R³, R⁴, and R⁵ are independently selected from the groupconsisting of hydrogen, alkanoyl having 2 to 6 carbons hydroxysubstituted alkanoyl having 2 to 6 carbons, and acyloxy-substitutedalkanoyl having 2 to 6 carbons, and wherein at least one of R¹, R², R³,R⁴, and R⁵ is other than hydrogen;

wherein R¹, R², R³, R⁴, R⁵, and R⁶ are independently selected from thegroup consisting of hydrogen, alkanoyl having 2 to 6 carbons,hydroxy-substituted alkanoyl having 2 to 6 carbons, andacyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at leastone of R¹, R², R³, R⁴, R⁵, and R⁶ is other than hydrogen;

wherein R¹, R², R³, and R⁴ are independently selected from the groupconsisting of hydrogen, alkanoyl having 2 to 6 carbons,hydroxy-substituted alkanoyl having 2 to 6 carbons, andacyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at leastone of R¹, R², R³, and R⁴ is other than hydrogen.

In a more particular aspect, the novel compound has the structure:

wherein R¹, R², R³, and R⁴ are independently selected from the groupconsisting of hydrogen, alkanoyl having 2 to 6 carbons,hydroxy-substituted alkanoyl having 2 to 6 carbons, andacyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at leastone of R¹, R², R³, and R⁴ is other than hydrogen.

The liquid compositions of the invention can be used in any of theutilities or applications disclosed for HVLCM or LVLCM in U.S. Pat. Nos.5,968,542 and 5,747,058, the entire contents of each of which are herebyincorporated by reference.

BRIEF DESCRIPTION OF DRAWINGS

The invention can be better understood by reference to the followingillustrative drawings, which are intended to illustrate and not to limitthe scope thereof.

FIG. 1 is a graph showing the cumulative release profiles forbupivacaine from decaglycerol tetraoleate and from a 1,6-hexanediollactate ε-hydroxycaproic acid according to the invention.

FIG. 2 is a graph showing the cumulative release profile for estradiolfrom a glycerol lactate glycolate according to the invention.

FIG. 3 is a graph showing the cumulative release profile forprogesterone from a 1,6-hexanediol lactate glycolate according to theinvention.

FIG. 4 is a graph showing the cumulative release profile for lysozymefrom hexaglycerol dioleate and a glycerol lactate glycolate according tothe invention.

FIG. 5 is a graph showing the cumulative release of cromolyn sodium frompoly(caprolactone) particles suspended in an SAIB/benzyl benzoateformulation according to the invention.

FIG. 6 is a graph showing the cumulative release of cromolyn sodium froma formulation of SAIB/benzyl benzoate containing polymer additiveaccording to the invention.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS Non-Water-Soluble, HighViscosity, Liquid Carrier Material

The high viscosity liquid carrier material should be selected that isnon-polymeric, non-water soluble, and has a viscosity of at least 5,000cP, (and optionally at least 10,000, 15,000; 20,000; 2,000 or even50,000 cP) at 37° C. that does not crystallize neat under ambient orphysiological conditions. The term “non-water soluble” refers to amaterial that is soluble in water to a degree of less than one percentby weight under ambient conditions. The term “non-polymeric” refers toesters or mixed esters having essentially no repeating units in the acidmoiety of the ester, as well as esters or mixed esters having acidmoieties wherein functional units in the acid moiety are repeated asmall number of times (i.e., oligomers). Generally, materials havingmore than five identical and adjacent repeating units or mers in theacid moiety of the ester are excluded by the term “nonpolymeric” as usedherein, but materials containing diners, trimers, tetramers, orpentamers are included within the scope of this term. When the ester isformed from hydroxy-containing carboxylic acid moieties that can furtheresterify, such as lactic acid or glycolic acid, the number of repeatunits is calculated based upon the number of lactide or glycolidemoieties, rather than upon the number of lactic acid or glycolic acidmoieties, where a lactide repeat unit contains two lactic acid moietiesesterified by their respective hydroxy and carboxy moieties, and where aglycolide repeat unit contains two glycolic acid moieties esterified bytheir respective hydroxy and carboxy moieties. Esters having 1 to about20 etherified polyols in the alcohol moiety thereof, or 1 to about 10glycerol moieties in the alcohol moiety thereof, are considerednonpolymeric as that term is used herein.

In a particular embodiment, the high viscosity liquid carrier material(HVLCM) decreases in viscosity, in some cases significantly, when mixedwith a solvent to form a low viscosity liquid carrier material (LVLCM)that can be administered as a medical or surgical implant, graft, orfilm, or mixed with a biologically active substance for controlleddelivery, or a combination thereof. The LVLCM/biologically activesubstance composition is typically easier to place in the body than aHVLCM/biologically active substance composition, because it flows moreeasily into and out of syringes or other implantation means, it also caneasily be formulated as an emulsion. The LVLCM can have any desiredviscosity, but its viscosity is generally lower than the correspondingHVLCM. As an example, viscosity ranges for the LVLCM of less thanapproximately 6,000 cP, more particularly, less than approximately 4,000cP, even more particularly, less than approximately 1,000 cP, and yeteven more particularly less than 200 cP, are typically useful for invivo applications.

The particular HVLCM used in the invention can be one or more of avariety of materials. Suitable materials include nonpolymeric esters ormixed esters of one or more carboxylic acids. In a particularembodiment, the ester is formed from carboxylic acids that areesterified with a polyol having from about 2 to about 20 hydroxymoieties, and which may include 1 to about 20 etherified polyols.Particularly suitable carboxylic acids for forming the acid moiety ofthe ester of the HVLCM include carboxylic acids having one or morehydroxy groups, e.g., those obtained by ring opening alcoholysis oflactones, or cyclic carbonates or by the alcoholysis of carboxylic acidanhydrides. Amino acids are also suitable for forming esters with thepolyol. In a particular embodiment, the ester or mixed ester contains analcohol moiety having one or more terminal hydroxy moieties that havebeen esterified with one or more carboxylic acids obtained byalcoholysis of a carboxylic acid anhydride, such as a cyclic anhydride.

Nonlimiting examples of suitable carboxylic acids that can be esterifiedto form the HVLCM of the invention include glycolic acid, lactic acid,ε-glycolic acid, lactic acid, ε-hydroxycaproic acid, serine, and anycorresponding lactones or lactams, trimethylene carbonate, anddioxanone. The hydroxy-containing acids may themselves be furtheresterified through the reaction of their hydroxy moieties withadditional carboxylic acid, which may be the same as or different fromother carboxylic acid moieties in the material. Suitable lactonesinclude, but are not limited to, glycolide, lactide, ε-caprolactone,butyrolactone, and valerolactone. Suitable carbonates include but arenot limited to trimethylene carbonate and propylene carbonate.

The alcohol moiety of the ester or mixed ester may be derived from apolyhydroxy alcohol having from about 2 to about 20 hydroxy groups, andas indicated above, may be formed by etherifying 1 to 20 polyolmolecules. Suitable alcohol moieties include those derived by removingone or more hydrogen atoms from: monofunctional C₁-C₂₀ alcohols,difunctional C₁-C₂₀ alcohols, trifunctional alcohols, hydroxy-containingcarboxylic acids, hydroxy-containing amino acids, phosphate-containingalcohols, tetrafunctional alcohols, sugar alcohols, monosaccharides, anddisaccharides, sugar acids, and polyether polyols. More specifically,the alcohol moieties may include one or more of: dodecanol, hexanediol,more particularly, 1,6-hexanediol, glycerol, glycolic acid, lactic acid,hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid, serine,ATP, pentaerythritol, mannitol, sorbitol, glucose, fructose, sucrose,glucuronic acid, polyglycerol ethers containing from 1 to about 10glycerol units, polyethylene glycols containing 1 to about 20 ethyleneglycol units.

In particular embodiments of the invention, at least one of thecarboxylic acid moieties of the esters or mixed esters of the inventioncomprise at least one oxy moiety In an even more particular embodiment,each of the carboxylic acid moieties comprise at least one oxy moiety.

In another particular embodiment, at least one of the carboxylic acidmoieties of the esters or mixed esters of the invention contains 2 to 4carbon atoms. In an even more particular embodiment, each of thecarboxylic acid moieties of the esters or mixed esters of the inventioncontain 2 to 4 carbon atoms.

In another more particular embodiment of the invention, at least one ofthe carboxylic acid moieties of the ester or mixed ester of theinvention has 2 to 4 carbon atoms and contains at least one oxy moiety.In another more particular embodiment of the invention, each of thecarboxylic acid moieties of the ester or mixed ester of the inventionhas 2 to 4 carbon atoms and contains at least one oxy moiety.

In a particular embodiment, the HVLCM may be sucrose acetate isobutyrate(SAIB) or some other ester of a sugar alcohol moiety with one or morealkanoic acid moieties.

In a particular embodiment, the invention includes compounds,compositions, and methods of use as described above, wherein the HVLCMhas a structure selected from the group consisting of:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently selectedfrom the group consisting of hydrogen, alkanoyl, hydroxy-substitutedalkanoyl, and acyloxy-substituted alkanoyl;

wherein at least three of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are otherhydrogen; and

wherein when R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, and R⁸ are selected formthe group consisting of acetyl and isobutyryl, at least three of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are acetyl;

wherein R¹, R², and R³ are independently selected from the groupconsisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, andacyloxy-substituted alkanoyl and wherein n is between 1 and 20;

R¹—O—(CH₂)_(n)—O—R²  III:

wherein n is an integer between 4 and 8, and R¹ and R² are independentlyselected from the group consisting of hydrogen, alkanoyl,hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl;

wherein in formulae IV and V, R¹, R², R³, R⁴, and R⁵ are independentlyselected from the group consisting of hydrogen, alkanoyl,hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl;

wherein in formulae VI and VII, R¹, R², R³, R⁴, R⁵, and R⁶ areindependently selected, from the group consisting of hydrogen, alkanoyl,hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl;

wherein R¹, R², R³, and R⁴ are, independently selected from the groupconsisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, andacyloxy-substituted alkanoyl.

In each of formulae I through VIII, one or more of the alkanoyl,hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl groupsmay comprise alkanoyl moieties having 2 to 6 carbon atoms, including thecarbonyl carbon. Moreover, in another more particular embodiment of theinvention, each of formulae I through VIII comprise at least onehydroxy-substituted or acyloxy-substituted alkanoyl moiety. In an evenmore particular embodiment, at least one of these hydroxy-substituted oracyloxy-substituted alkanoyl moieties comprise alkanoyl moieties having2 to 6 carbon atoms, including the carbonyl carbon.

The acyl groups forming the acyloxy substituents of the invention may beany moiety derived from a carboxylic acid in accordance with thecommonly accepted definition of the term “acyl”. More particularly, theacyl groups of the compositions of the invention may be of the formR⁹CO—, where R⁹ is optionally oxy-substituted alkyl of 2-6 carbon atoms.This oxy-substitution may take the form of hydroxy substitution, orsubstitution with additional acyl moieties. For example R⁹ may be anoligomer of oxy-substituted carboxylic acids, linked by ester bondingbetween the hydroxy of one acid and the carboxy of another acid. In amore particular example, R⁹ may comprise 1 to 5 lactide or glycolideunits, where a lactide unit contains two lactic acid moieties esterifiedtogether and a glycolide unit contains two glycolic acid moietiesesterified together. Alternatively, R⁹ may contain mixed lactide andglycolide units, or may contain mixed lactic acid and glycolic acid,without the presence of lactide or glycolide units.

Particular HVLCM materials include components according to formulae IIor III, wherein R¹, R², and R³ are independently lactoyl, polylactoyl,ε-caproyl, hydroxyacetyl, or polyhydroxyacetyl, in particular,polylactoyl and s-caproyl, or polylactoyl and polyhydroxyacetyl.

The use of relatively small chain (2 to 6 carbon atoms), oxy-substitutedcarboxylic acid moieties in the ester or mixed ester of the invention isadvantageous. When these acid moieties are present in the form ofoligomeric esters (i.e., a subsequent acid moiety joined to the previousacid moiety through esterification of the subsequent carboxy with theprevious oxy), hydrolysis of the material is considerably easier thanfor oligomers made with more than 6 carbon atoms because the material ismore hydrophilic. in general, for drug delivery it is desired that theHVLCM be water insoluble, but it may be somewhat hydrophilic. Ingeneral, HVLCMs synthesized with more hydrophilic units (as determinedby a higher O:C ratio) will be expected to absorb water more rapidly anddegrade more quickly. For example, a HVLCM made by covalently linking 4moles of glycolide to one mole of glycerol will be expected to absorbwater more rapidly and degrade more quickly than a HVLCM made bycovalently linking 2 moles of glycolide and 2 moles of lactide to onemole of glycerol. Similar increases can be expected for more flexiblemolecules and for more branched, spherical molecules based on freevolume arguments. Use of flexible and branched molecules may also havethe benefit of lowering the viscosity of the LVLCM. Using carboxylicacids and/or polyols of different chain length and using carboxylicacids having oxy-substitution allows a precise control of the degree ofhydrophilicity and of the solubility of the resulting ester. Thesematerials are sufficiently resistant to dissolution in vivo that theyare able to provide a controlled release of bioactive substances intothe body accompanied or followed by oxy bonds hydrolyzing in vivo.

In an even more particular embodiment, the invention excludes theacetate and isobutyrate ester of sucrose having a ratio of acetate toisobutyrate acid moieties of 2:6. However, sucrose acetate isobutyrateester having a ratio of acetate to isobutyrate moieties of 2:6 isincluded within the scope of the invention for use in aerosolformations, as well as for the delivery of lysozyme, paclitaxel,5-fluorouracil, and antiretroviral drugs like AZT and ddC, as describedand exemplified below. This material can be made according to theprocedures described in U.S. Pat. No. 2,931,802.

In general, the HVLCM esters of the invention can be made by reactingone or more alcohols, in particular one or more polyols, which will formthe alcohol moiety of the resulting esters with one or more carboxylicacids, lactones, lactams, carbonates, or anhydrides of the carboxylicacids which will form the acid moieties of the resulting esters. Theesterification reaction can be conducted simply by heating, although insome instances addition of a strong acid or strong base esterificationcatalyst may be used. Alternatively, an esterification catalyst such asstannous 2-ethylhexanoate can be used. The heated reaction mixture, withor without catalyst, is heated with stirring, then dried, e.g., undervacuum, to remove any unreacted starting materials, to produce a liquidproduct. Sucrose acetate isobutyrates can be made by following theprocedures described in U.S. Pat. No. 2,931,802.

In this regard, the polyol can be viewed as an oligomerizationinitiator, in the sense that it provides a substrate for esterificationof carboxylic acids, in particular, of oligomers of lactide, glycolide,or other esterified hydroxy-substituted carboxylic acids.

Solvents

As described above, in one embodiment of the invention, the HVLCM can bemixed with a viscosity lowering solvent to form a lower viscosity liquidcarrier material (LVLCM), which can then be mixed with the biologicallyactive substance to be delivered, prior to administration. Thesesolvents can be water soluble, non-water soluble, or water miscible, andcan include, acetone, benzyl alcohol, benzyl benzoate,N-(betahydroxyethyl)lactamidebutylene glycol, caprolactam, caprolactone,corn oil, decylmethylsulfoxide, dimethyl ether, dimethyl sulfoxide,1-dodecylazacycloheptan-2-one, ethanol, ethyl acetate, ethyl lactate,ethyl oleate, glycerol, glycofurol (tetraglycol), isopropyl myristate,methyl acetate, methyl ethyl ketone, N-methyl-2-pyrrolidone, MIGLYOLs®(esters of caprylic and/or capric acids with glycerol or alkyleneglycols, e.g., MIGLYOL® 810 or 812 (caprylic/capric triglycerides),MIGLYOL® 818 (caprylic/capric/linoleic triglyceride), MIGLYOL® 829(caprylic/capric/succinic triglyceride), MIGLYOL® 840 (propylene glycoldicaprylate/caprate)), oleic acid, peanut oil, polyethylene glycol,propylene carbonate, 2-pyrrolidone, sesame oil, SOLKETAL([±]-2,2-dimethyl-1,3-dioxolane-4-methanol), tetrahydrofuran,TRANSCUTOL® (diethylene glycol monoethyl ether, carbitol), triacetin,triethyl citrate, diphenyl phthalate, and combinations thereof.Additionally, if the composition is to be applied as an aerosol, e.g.for topical application, the solvent may be or may include one or morepropellants, such as CFC propellants like trichlorofluoromethane anddichlorofluoromethane, non-CFC propellants like tetrafluoroethane(R-134a), 1,1,1,2,3,3,3-heptafluoropropane (R-227), dimethyl ether,propane, and butane.

Particularly suitable solvents and/or propellants include benzylbenzoate, benzyl alcohol, triacetin, triethyl citrate, dimethylsulfoxide, ethanol, ethyl lactate, glycerol, glycofurol (tetraglycol),N-methyl-2-pyrrolidone, MIGLYOL® 810, polyethylene glycol, propylenecarbonate, 2-pyrrolidone, and tetrafluoroethane.

Other possible solvents include perfluorodecalin,perfluorotributylamine, methoxyflurane, glycerolformal,tetrahydrofurfuryl alcohol, diglyme, and dimethyl isosorbide.

When the composition is used as a LVLCM in conjunction withadministration of a biologically active substance, it should contain asolvent that the HVLCM is soluble in. In certain instances, thesubstance to be delivered is also soluble in the solvent. The solventshould be non-toxic and otherwise biocompatible, Solvents that are toxicshould not be used for pharmaceutical or agricultural purposes. Thesolvents used to inject the composition into animals should not causesignificant tissue irritation or necrosis at the site of implantation,unless irritation or necrosis is the desired effect.

In one embodiment, the solvent should be at least water soluble, so thatit will diffuse quickly into bodily fluids or other aqueous environment,causing the composition to coagulate or solidify. In another embodiment,the solvent is not completely miscible with water or bodily fluids sothat diffusion of the solvent from the composition, and thecorresponding increase in viscosity of the composition, are slowed.Suitable solvents that have this property, at least to some extent,include benzyl benzoate, MIGLYOL® 810, benzyl alcohol, andtriethylcitrate. Benzyl alcohol can be particularly suitable, as it alsoprovides an anesthetizing effect, which can relieve discomfort resultingfrom injection.

When esters of 1,6-hexanediol or glycero are used as the HVLCM, somepossible solvents are ethanol, 1-methylpyrrolidone, propylene carbonate,and PEG 400.

The solvent is typically added to the compositions in an amount in therange from about 0.5 percent to about 99.7 percent, more particularlyfrom about 1 percent to about 95 percent by weight, more particularlyfrom about 5 to about 90 wt %, relative to the total weight of thecomposition. Even. more particularly, the solvent is present in thecomposition in an amount in the range from about 10 percent to about 55percent by weight. Other particular ranges include from about 10 percentto 50 percent to percent by weight, and from about 10 to about 30percent by weight.

A further embodiment involves the use of solvents that are not solventsfor the HVLCM such that when. combined with the HVLCM singularly or incombination with a solvent for the HVLCM, the resulting compositionforms an emulsion. Such emulsions may contain the HVLCM in the dispersedphase such as in the case of SAIB/MIGLYOL® mixtures that are emulsifiedin water or glycerol, or they may contain the HVLCM as a component ofthe continuous phase such as in the case of an aqueous solution that isemulsified in the HVLCM or a solution of the HVLCM in a water immisciblesolvent.

Substance to be Delivered

When the HVLCM or LVLCM is to be used as a vehicle for delivery orcontrolled release of a substance to an animal or plant, this substancemay be any substance that exhibits a desired property. In a particularembodiment, the substance is a biologically active substance.

The term “biologically active substance” as used herein refers to aninorganic or organic molecule including a drug, peptide, protein,carbohydrate (including monosaccharides, oligosaccharides, andpolysaccharides), nucleoprotein, mucoprotein, lipoprotein, syntheticpolypeptide or protein, or a small molecule linked to a protein,glycoprotein, steroid, nucleic acid (any form of DNA, including cDNA, orRNA, or a fragment thereof), nucleotide, nucleoside, oligonucleotides(including antisense oligonucleotides), gene, lipid, hormone, vitamin,including vitamin C and vitamin E, or combination thereof, that causes abiological effect when administered in vivo to an animal, including butnot limited to birds and mammals, including humans.

Suitable proteins include, but are not limited to, human growth hormone,fibroblast growth factor (FGF), erythropoietin (EPO), platelet derivedgrowth factor (PDGF), granulocyte colony stimulating factor (g-CSF),bovine somatotropin (BST), tumor necrosis factor (TNF), transforminggrowth factor-beta (TGF-Beta), interleukins, insulin, and interferons,such as α-interferon, β-interferon, and the like.

The term drug, as used herein, refers to any substance used internallyor externally as a medicine for the treatment, cure, or prevention of adisease or disorder, and includes but is not limited toimmunosuppressants, antioxidants, anesthetics, analgesics,chemotherapeutic agents, steroids (including retinoids), hormones,antibiotics, antivirals, antifungals, antiproliferatives,antihistamines, anticoagulants, antiphotoaging agents, melanotropicpeptides, nonsteroidal and steroidal anti-inflammatory compounds,antipsychotics, and radiation absorbers, including UV-absorbers.

The term biologically active substance also includes agents such asinsecticides, pesticides, fungicides, rodenticides, and plant nutrientsand growth promoters.

In one embodiment, the composition functions as a vaccine and thesubstance to be delivered is an antigen. The antigen can be derived froma cell, bacteria, or virus particle, or portion thereof. As definedherein, antigen may be a protein, peptide, polysaccharide, glycoprotein,glycolipid, nucleic acid, or combination thereof, which elicits animmunogenic response in an animal, for example, a mammal, bird, or fish.As defined herein, the immunogenic response can be humoral orcell-mediated. In the event the material to which the immunogenicresponse is to be directed is poorly antigenic, it may be conjugated toa carrier such as albumin or to a hapten, using standard covalentbinding techniques, for example, with one of the several commerciallyavailable reagent kits.

Examples of preferred antigens include viral proteins such as influenzaproteins, human immunodeficiency virus (HIV) proteins, and hepatitis A,B, or C proteins, and bacterial proteins, lipopolysaccharides such asgram negative bacterial cell walls and Neisseria gonorrhea proteins, andparvovirus. The composition of the invention can also be used to elicitboth mucosal and systemic immune responses by administration of theHVLCM of the invention, optionally with a solvent to decrease itsviscosity as described above, in combination with an immunogenicmaterial, in a vaccine that is a administered to a mucosal surface,e.g., intranasally, intravaginally, or intrarectally. The immunogenicmaterial may be any immunogenic agent whose delivery to mucosal tissueis desired. In an even more particular aspect of this embodiment, theHVLCM or LVLCM is selected from formulae II through VIII above. Vaccinesof this type can be prepared and administered by delivering animmunogenic material to the mucosal tissues, particularly to themucosally associated lymphoid tissues of animals, particularly mammals,Administering immunogenic materials, in particular, immunogenic materialcombined with a carrier containing the non-polymeric, non-water-soluble,high viscosity liquid and a solvent therefore to the folliculi lymphaticaggregati which are found in the mucosal tissues can be an effectivedelivery technique. The solvent rapidly dissipates, resulting in ahighly viscous liquid formulation that holds the immunogenic materialover the muscosal tissue and allows the immunogenic material tostimulate a mucosal immune response and/or a systemic immune response.Administration of the formulation may include aerosolizing theformulation or a water emulsion thereof and administering thisformulation intranasally, intravaginally (e.g., as a douching liquid,vaginal suppository, or bougie), or intrarectally (e.g., as an enema,suppository or bougie). In particular embodiments, the solvent can be,or the formulation can include, a penetration enhancer that facilitatesthe absorption of the immunogenic material into the lymphatic tissue.The non-polymeric, non-water-soluble, high viscosity liquid materialprovides controlled release of the immunogenic material from a viscousliquid film that forms over the lymphoid tissue.

The immunogenic material may be any immunogenic agent whose delivery tomucosal tissue, and in particular to mucosally associated lymphoidtissue (MALT), is desired. Even more particularly, the mucosal tissuemay be nasally associated lymphoid tissue, Waldeyer's ring, or analogoustissue in non-human species. Examples of suitable immunogenic materialsinclude, but are not limited to, antigens to vaccinate against viral,bacterial, protozoan, fungal diseases such as respiratory syncytial,parainfluenza viruses, Hemophilus influenza, Bordetella pertussisNeisseria gonorrhoeae, Streptococcus pneumoniae, and Plasmodiumfalciparum or other diseases caused by pathogenic micro-organisms,antigens to vaccinate against diseases caused by macro-organisms such ashelminthic pathogens, antigens to vaccinate against allergens.

In another embodiment, the composition functions as a controlled releasecomposition for reproductive therapy, in humans or animals. For example,the HVLCM or LVLCM may be combined with gonadotropin releasing hormoneor its analogs or agonists. In a particular aspect of this embodiment,the HVLCM or LVLCM is not SAIB having an acetate to butyrate ratio of2:6. In an even more particular aspect of this embodiment, the HVLCM orLVLCM is selected from formulae II through VIII above. Thesecompositions can be prepared and administered by following theprocedures described for SAIB in U.S. Pat. No. 6,051,558, the entirecontents of which are hereby incorporated by reference.

Non-limiting examples of pharmacological materials includeanti-infectives such as nitrofurazone, sodium propionate, antibiotics,including penicillin, tetracycline, oxytetracycline, chlorotetracycline,bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin,chloramphenicol, erythromycin, and azithromycin; sulfonamides, includingsulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine,sulfamerazine, and sulfisoxazole, and anti-virals including idoxuridine;antiallergenics such as antazoline, methapyritene, chlorpheniramine,pyrilamine prophenpyridamine, hydrocortisone, cortisone, hydrocortisoneacetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone,triamcinolone, medrysone, prednisolone, prednisolone 21-sodiumsuccinate, and prednisolone acetate; desensitizing agents such asragweed pollen antigens, hay fever pollen antigens, dust antigen andmilk antigen; vaccines such as smallpox, yellow fever, distemper, hogcholera, chicken pox, antivenom, scarlet fever, diphtheria toxoid,tetanus toxoid, pigeon pox, whooping cough, influenzae rabies, mumps,measles, poliomyelitic, and Newcastle disease; decongestants such asphenylephrine, naphazoline, and tetrahydrazoline; miotics andanticholinesterases such as pilocarpine, esperine salicylate, carbachol,diisopropyl fluorphosphate, phospholine iodide, and demecarium bromide;parasympatholytics such as atropine sulfate, cyclopentalate,homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine; sympathomimetics such as epinephrine;antipsychotics, such as olanzapine, risperidone; narcotic antagonists,such as naltrexone, naloxone, nalnothene; sedatives and hypnotics suchas pentobarbital sodium, phenobarbital, secobarbital sodium, codeine,(a-bromoisovaleryl)urea, carbromal; psychic energizers such as3-(2-aminopropyl)indole acetate and 3-(2-aminobutyl)indole acetate;tranquilizers such as reserpine, chlorpromayline, and thiopropazate;anesthetics, such as benzocaine, bupivacaine, etidocaine, lidocaine,mepivacaine, pramoxine, prilocaine, procaine, proparacaine, ropivacaine,tetracaine, levobupivacaine, chloroprocaine, butacaine, propoxycaine,phenacaine, hexylcaine, isobucaine, cyclomethycaine, benoxinate,diperodan, dibucaine, meprylcaine, dimetisoquin, pramoxine, butamben,dyclonine (with and without augmenting agents such as dexamethasone orepinephrine); tricyclic antidepressants such as amitriptyline ornortryptyline; androgeric steroids such as methyl-testosterone andfluorymesterone; estrogens such as estrone, 171-estradiol, ethinylestradiol, and diethyl stilbestrol; progestational agents such asprogesterone, megestrol, melengestrol, chlormadinone, ethisterone,norethynodrel, 19-norprogesterone, norethindrone, medroxyprogesteroneand 17-hydroxy-progesterone; humoral agents such as the Prostaglandins,for example PGEI, PGE2 and PGF2; antipyretics such as aspirin, sodiumsalicylate, and salicylamide; antispasmodics such as atropine,methantheline, papaverine, and methascopolamine bromide; antimalarialssuch as the 4-aminoquinolines, 8 aminoquinolines, chloroquine, andpyrimethamine, antihistamines such as diphenhydramine, dimenhydrinate,tripelennamine, perphenazine, and chlorphenazine; cardioactive agentssuch as dibenzhydroflume thiazide, fumethiazide, chlorothiazide, andaminotrate; statins, such as atorvastatin, cerivastatin, fluvastatin,lovastatin, pravastatin, simvastatin, and related compounds;antiasthmatics, such as cromolyn; bone resorption prevention agents,such as bisphosphonates, including as nonlimiting examples alendronate,risendronate, zolendronate, pamidronate, and ibandronate; calciumregulating hormones, such as calcitonin; nutritional agents such asvitamins, natural and synthetic bioactive peptides and proteins,including growth factors, cell adhesion factors, cytokines, andbiological response modifiers.

The active compound is included in the composition in an amountsufficient to deliver to the host animal or plant an effective amount toachieve a desired effect. The amount of drug or biologically activeagent incorporated into the composition depends upon the desired releaseprofile, the concentration of drug required for a biological effect, andthe desired period of release of the drug.

The concentration of active compound in the composition will also dependon absorption, inactivation, and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated, it is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcomposition. The composition may be administered in one dosage, or maybe divided into a number of smaller doses to be administered at varyingintervals of time.

The biologically active substance is typically present in thecomposition in the range from about 0.1 percent to about 90 percent byweight, more particularly from about 0.5 percent to about 70 percent byweight relative to the total weight of the composition, and moretypically, between approximately 1 percent to about 50 percent byweight. However, ranges having upper endpoints as low as about 40%, 30%,20%, or 10% can be used, as can ranges having lower limits as high asabout 5%, 3%, or 2%. For very active agents, such as growth factors,preferred ranges are less than 1% by weight, and possibly less than0.0001%.

Both soluble and insoluble substances can be distributed in the HVLCM orLVLCM for controlled delivery. Moreover, the formulations containingbiologically active substances and an HVLCM or LVLCM may be furtherformulated with polymeric excipients to provide a drug delivery matrixwith modified properties, for example a faster or slower degradationrate. The resulting composition may be formed into microspheres, or intoa macroscopic implant, or other geometries and sizes according totechniques known in the art. Alternatively, a pre-formed microsphere,implant, or polymer/drug particle with a biologically active substanceor substances incorporated therein can be combined with the HVLCM orLVLCM.

Microspheres may be prepared by a number of methods known in the art, aswell as methods described in U.S. Pat. Nos. 6,291,013 and 6,440,493. Thepolymer/drug particle may be created by melt extrusion, granulation,solvent mixing, or absorption, or the drug may be adsorbed onto apolymer matrix, such as an ion exchange resin. The resulting material,when combined with a biologically active agent and LVLCM, may beadministered orally or parenterally. In other embodiments, the drug maybe combined with a non-polymeric material, such as calcium phosphate orsucrose, to provide layering/barrier properties that lengthendegradation. The HVLCM or LVLCM will form an secondary barrier toprovide enhanced drug delivery. The HVLCM or LVLCM phase may or may notcontain other biologically active substances, according to the specificbiological requirement. These other biologically active substances maybe any of those described above, provided that the biologically activesubstance must be suitable for incorporation into microspheres orimplants according to techniques known in the art.

Additives

A variety of additives can optionally be added to the HVLCM or LVLCM tomodify the properties of the material as desired, and in particular tomodify the release properties of the composition with respect tobiologically active substances contained therein. The additives can bepresent in any amount which is sufficient to impart the desiredproperties to the composition. The amount of additive used will ingeneral be a function of the nature of the additive and the effect to beachieved, and can be easily determined by the routineer. Suitableadditives are described in U.S. Pat. No. 5,747,058, the entire contentsof which are hereby incorporated by reference. More particularly,suitable additives include water, biodegradable polymers,non-biodegradable polymers, natural oils, synthetic oils, carbohydratesor carbohydrate derivatives, inorganic salts, BSA (bovine serumalbumin), surfactants, organic compounds, such as sugars, and organicsalts, such as sodium citrate. Some of these classes of additives aredescribed in more detail below. in general, the less water soluble,i.e., the more lipophilic, the additive, the more it will decrease therate of release of the substrate, compared to the same compositionwithout the additive. In addition, it may be desirable to includeadditives that increase properties such as the strength or the porosityof the composition.

The addition of additives can also be used to lengthen the delivery timefor the active ingredient, making the composition suitable for treatmentof disorders or conditions responsive to longer term administration.Suitable additives in this regard include those disclosed in U.S. Pat.No. 5,747,058. In particular, suitable additives for this purposeinclude polymeric additives, such as cellulosic polymers andbiodegradable polymers Suitable cellulosic polymers include celluloseacetates, cellulose ethers, and cellulose acetate butyrates. Suitablebiodegradable polymers include polylactones, polyanhydrides, andpolyorthoesters, in particular, polylactic acid, polyglycolic acid,polycaprolactone, and copolymers thereof.

When present, the additive is typically present in the compositions inan amount in the range from about 0.01 percent to about 20 percent byweight, more particularly from about 0.1 percent to about 20 percent byweight, relative to the total weight of the composition, and moretypically, is present in the composition in an amount in the range fromabout 1, 2, or 5 percent to about 10 percent by weight. Certainadditives, such as buffers, are only present in small amounts in thecomposition.

The following categories are nonlimiting examples of classes ofadditives that can be employed in the composition.

Given the disclosure herein and the objects to be achieved, one of skillin the art will easily know how to select other additives to achieve adesired purpose. All of these embodiments are considered to fall withinthe disclosed invention.

A. Biodegradable Polymers

One category of additives are biodegradable polymers and oligomers. Thepolymers can be used to alter the release profile of the substance to bedelivered, to add integrity to the composition, or to otherwise modifythe properties of the composition. Non-limiting examples of suitablebiodegradable polymers and oligomers include: poly(lactide),poly(lactide-co-glycolide), poly(glycolide), poly(caprolactone),polyamides, polyanhydrides, polyamino acids, polyorthoesters,polycyanoacrylates, poly(phosphazines), poly(phosphoesters),polyesteramides, polydioxanones, polyacetals, polyketals,polycarbonates, polyorthocarbonates, degradable polyurethanes,polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,polyalkylene succinates, poly(malic acid), chitin, chitosan, andcopolymers, terpolymers, oxidized cellulose, or combinations or mixturesof the above materials.

Examples of poly(α-hydroxy acid)s include poly(glycolic acid),poly(DL-lactic acid) and poly(L-lactic acid), and their copolymers.Examples of polylactones include poly(ε-caprolactone),poly(δ-valerolactone) and poly(γ-butyrolactone).

While not wishing to be bound by any theory, it is believed that whenthat when the composition contains a biodegradeable polymer, a portionof the polymer may precipitate or coagulate at the surface of thecomposition as the solvent diffuses away from the material afteradministration to the patient. The polymer may have been added as arelease modifying agent to affect the release of a biologically activecompound, or may have been added as part of a composition containingpreformed microspheres, implants, or ground polymer particles. Theprecipitation or coagulation of the polymer forms a skin at leastpartially surrounding the liquid core of the composition. This skin isporous, and allows the solvent to continue to diffuse through it intosurrounding tissue. The rate of solvent release and the extent offormation of the skin, as well as its porosity, can be controlled by theamount and type of solvent and polymer used in the composition,

B. Non-Biodegradable Polymers

Another additive for use with the present compositions arenon-biodegradable polymers. Non-limiting examples of nonerodiblepolymers which can be used as additives include: polyacrylates,ethylene-vinyl acetate polymers, cellulose and cellulose derivatives,acyl substituted cellulose acetates and derivatives thereof,non-erodible polyurethanes polystyrenes, polyvinyl chloride, polyvinylfluoride, polyvinyl (imidazole), chlorosulphonated polyolefins,polyethylene oxide, and polyethylene.

Preferred non-biodegradable polymers include polyvinyl pyrrolidone,ethylene vinylacetate polyethylene glycol, cellulose acetate butyrate(“CAB”) and cellulose acetate propionate (“CAP”).

C. Oils and Fats

A further class of additives which can be used in the presentcompositions are natural and synthetic oils and fats. Oils derived fromanimals or from plant seeds of nuts typically include glycerides of thefatty acids, chiefly oleic, palmitic, stearic, and linolic. As a rulethe more hydrogen the molecule contains the thicker the oil becomes.

Non-limiting examples of suitable natural and synthetic oils includevegetable oil, peanut oil, medium chain triglycerides, soybean oil,almond oil, olive oil, sesame oil, fennel oil, camellia oil, corn oil,castor oil, cotton seed oil, and soybean oil, either crude or refined,and medium chain fatty acid triglycerides.

Fats are typically glyceryl esters of higher fatty acids such as stearicand palmitic. Such esters and their mixtures are solids at roomtemperatures and exhibit crystalline structure. Lard and tallow areexamples. In general oils and fats increase the hydrophobicity of theHVLCM, slowing degradation and water uptake.

D. Carbohydrates and Carbohydrate Derivatives

Another class of additives which can be used in the present compositionsare carbohydrates and carbohydrate derivatives. Non-limiting examples ofthese compounds include monosaccarides (simple sugars such as fructoseand its isomer glucose (dextrose); disaccharides such as sucrose,maltose, cellobiose, and lactose; and polysaccharides,

E. Multivalent Metals

Another class of additives includes multivalent metals, such as zinc,useful in ionic form as protein stabilizers. The zinc may b present inthe formulation as zinc carbonate, zinc acetate, zinc sulfate, zincchloride, or other zinc salts as appropriate. Other non-limitingexamples of compounds to provide metal cations in the formulationinclude magnesium carbonate, calcium carbonate, magnesium acetate,magnesium sulfate, magnesium chloride, magnesium oxide, magnesiumhydroxide, and the like. The amount of such agents used in theformulation will depend upon the amount of protein in the formulationand the nature of the interaction between the protein and thestabilizer.

Uses of the LVLCM and HVLCM Compositions

The composition described herein can be administered to the host througha variety of methods which can vary depending on the result to beachieved. When the host is an animal, such as a human, the compositioncan be administered, for example, topically, systematically (forexample, mucosally (orally, rectally, vaginally, or nasally),parenterally (intravenously, subcutaneously, intramuscularly, orintraperitoneally), or through the pulmonary system, in an appropriatecarrier, if desired. When the composition is used for administration tohumans or animals, or used for agricultural purposes, it can be appliedvia injection, pouring, spray dip, aerosol, or coating applicator.Aerosols or mists of the composition can be administered using anaerosol propellant, e.g., for topical administration, or using asuitable nebulizer, e.g., for pulmonary, nasal, or oral mucosaladministration. In addition, pericardial administration may be used whenthe composition is used to deliver compounds such as growth factors(e.g., transforming growth factors (TGF's), fibroblast growth factors(FGF's), vascular endothelial growth factor (VEGF)), antiarrhythmics(e.g., sotalol, propanolol), antianginals, and antihypertensives.

Preferably, for pharmaceutical or veterinary purposes, the presentcompositions are administered as liquids via injection, or in anaerosol, paste or emulsion. When administered via injection as a LVLCM,if a water-soluble solvent has been used in the composition, the solventleaches into the aqueous fluid of the host, forming a highly viscousdepot for the controlled delivery of substances or a coating for tissuethat can prevent or minimize adhesions. As explained above, these of awater soluble solvent in making the LVLCM significantly decreases theleaching time. When used in an aerosol, the small amount of solvent inthe solution evaporates upon application allowing the LVLCM to set-up asan HVLCM. Alternatively, the aerosol or emulsion may be prepared withouta solvent, In this situation, the aerosol propellant can also functionas a solvent. Formation of aerosols and emulsions can be accomplishedusing techniques known to those skilled in the art. See, for example,Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug DeliverySystems, sixth ed., 1995.

In addition to the uses described above, the HVLCM and LVLCM materialscan be administered through osmotic pumps. In one embodiment, the deviceis designed to be implanted in the tissue of the patient, and designedto effect sustained release over time. In a different embodiment, thedevice is orally administrable, such as an OROS-type osmotic pump. Anexample of an implantable osmotic pump suitable for use with thecompositions of the invention is the DUROS pump, described in U.S. Pat.Nos. 5,985,305 and 5,728,396, and in WO 97/27840, the entire contents ofeach of which are incorporated herein by reference.

It is also possible to administer the compositions of the inventionusing a porous or nonporous tube, desirably made of extrudedbiodegradable polymer. The tube may be prepared with varying degrees ofporosity depending on the characteristics of the composition and therelease characteristics desired. The composition of the invention isinserted into the tube, and the ends of the tube may be left open,allowing biologically active compound to diffuse out of the ends of thetube, or may be closed off with additional porous or nonporous polymer.Porous endcaps and porous tubes allow active compound to diffuse throughthe pores over time. Nonporous endcaps, as well as nonporous tubes,allow biologically active compounds that are soluble in the polymer todiffuse through it and into surrounding tissues. Nonporous materialsthat are not solvents for the biologically active compound, but that arebiodegradable, will release the active compounds when they degradesufficiently. The compositions of the invention may be prepared andstored as multi-component systems until ready for administration. Thenumber of different components will depend, in part, on thecharacteristics of the composition. For example, one component maycontain the HVLCM or LVLCM, while other components contain the activecompound or compounds to be administered. Prior to administration, thecomponents are combined and mixed, e.g., to achieve a homogeneouscomposition, which can then be administered to the patient, Solvents oradditives may be added to one or all of the components, or may form aseparate component, which is also mixed with the others prior toadministration. Separation of the composition into a multicomponentmixture allows the storage conditions for each component to beoptimized, and minimizes any detrimental interactions between componentsover time. The result is increased storage stability.

The compositions can be used to form protective tissue coatings, and inparticular, can be used to prevent the formation of surgical adhesions.The HVLCM can adhere to the surrounding tissue or bone, and can thus beinjected subdermally like collagen to build up tissue or to fill indefects. It can also be injected into wounds including burn wounds toprevent the formation of deep scars. The degradation time of the HVLCMcan be modulated, for example, by using a polymer as an additive to theHVLCM. Then the implant formed by the HVLCM will slowly biodegradewithin the body and allow natural tissue to grow and replace the implantas it disappears. These compositions may optionally contain biologicallyactive substances including but not limited to, anesthetics, analgesics,antibiotics, and antinflammatories.

As indicated above, the HVLCM and LVLCM materials of the invention canbe used not only for the controlled release and delivery of substances,such as bioactive substances, to plants or animals, but also as medicalor surgical devices, as described in U.S. Pat. No. 5,968,542, the entirecontents of which are incorporated by reference.

Device utilities for the compositions of the invention include, but arenot limited to blocking surgical adhesions, void filling, guided tissueregeneration, inducing hemostasis, tissue adhesive, scaffolding, andwound dressing. Each of these applications can optionally includerelease of a biologically active substance, or drug delivery. Forexample, the nonpolymeric ester or mixed ester composition as a wounddressing readily accommodates various growth factors to acceleratehealing of the wound. In general, for these utilities a composition canbe used having the non-polymeric non-water-soluble liquid carriermaterial present in an amount from about 99.5 percent to about 25percent by weight, relative to the total weight of the composition.These compositions can be diluted with a solvent, including but notlimited to one or more of ethanol, dimethylsulfoxide, ethyl lactate,ethyl acetate, benzyl alcohol, triacetin, 2-pyrrolidone,N-methylpyrolidone, propylene carbonate, glycofurol, capric/caprylic;triglycerides, benzyl benzoate, ethyl oleate, isopropyl myristate,triethyl citrate, and any aerosol propellant, to a concentration of thenon-polymeric non-water-soluble liquid carrier material of about 10 toabout 90% by weight, calculated based on the total weight of thecomposition, to obtain an implantable or sprayable composition.

For blocking surgical adhesions, a sprayed-on or painted-on film toblock adhesion of similar or dissimilar organs is suitable. Thenonpolymeric ester or mixed ester composition is formulated in any of avariety of solvents, including ethanol, ethyl lactate,N-methyl-2-pyrrolidone, or any common aerosol propellant, dimethylether, or any propellant with or without an additive, and can be appliedas an aerosol spray. The resulting film may effect adhesion, cohesion,degradation or porosity, or a combination thereto.

For void filling, the nonpolymeric ester or mixed ester composition istypically suitable like collagen for cosmetic repair. In relatedapplications, the nonpolymeric ester or mixed ester composition isuseful for holding bone chips together in a fracture, and may optionallyinclude an anesthetic, antibiotic, or growth factor for local delivery.

Guided tissue regeneration is another application, such as periodontalrepair to block epithelial migration. Advantageously, the compositionsof the present invention are applied from solution. Typical drugsincorporated into these compositions for guided tissue regenerationinclude but are not limited to a variety of growth factors and cellreattachment actors.

Hemostasis or stopping blood flow is another utility, typically in asurgical setting. The compositions of the present invention arebiodegradable. Suitable additives include, but are not limited topolyvinyl alcohol, polyethylene glycol or carboxymethyl cellulose.Suitable solvents include ethyl lactate and propylene carbonate.

A spray-on or paint-on formulation of the nonpolymeric ester or mixedester composition is suitable as a tissue adhesive for wound closure,either as a primary sealant or in conjunction with sutures or staples.Suitable additives include but are not limited to carboxymethylcelluloseor polyvinylpyrrolidone. Suitable solvents include but are not limitedto propylene carbonate, ethyl lactate, glycofural, dimethylsulfoxide,2-pyrrolidone, N-methyl-2-pyrrolidone, and ethanol. Biologically activesubstances incorporated into these compositions for tissue adhesioninclude but are not limited to antibiotics, anti-inflammatory compounds,analgesics, anesthetics and growth factors.

Scaffolding is another device utility for the compositions of thepresent invention, and is particularly adaptive to new tissue growth. Atypical formulation includes polyvinylpyrrolidone and tricalciumphosphate. The scaffolding provides a matrix suitable for the attachmentand growth of bone or nerve cells. Biologically active substancesincorporated into these compositions for scaffolding include but are notlimited to growth factors.

Another application of the compositions of the present invention is awound dressing, with or without appropriate drugs incorporated therein.The wound dressing functions to protect the wound and accelerate thehealing process. In one typical application, the nonpolymeric ester ormixed ester composition is applied as an aerosol spray. Biologicallyactive substances incorporated into these compositions in wound dressinginclude but are not limited to antibiotics, such as amikacin,anti-inflammatory compounds, analgesics, anesthetics, or growth factorssuch as fibroblast growth factors. Alternatively, the nonpolymeric esteror mixed ester composition with the biologically active substance isapplied to a gauze or other matrix material which is then applied to thewound.

Whether the compositions of the invention are used as for controlledrelease delivery of biologically active substances, or as devices orimplants, the compositions can have very high viscosities. As describedabove, the HVLCM materials have a viscosity at 37° C. of at least 5,000cP. In a more particular embodiment, the HVLCM materials haveviscosities above 10,000 cP, more particularly above 15,000 cP, evenmore particularly above 20,000, 25,000, or 50,000 cP at 37° C.

As apparent from the discussion above, the amount of HVLCM present inthe composition may vary considerably, depending upon such factors asthe number and amount of other components included in the composition,the use to which the composition will be put, and the method ofadministration of the composition. In general the HVLCM can be presentin amounts as high as 99.5 wt % to much lower amounts, provided that theHVLCM continues to perform its function as a carrier material. Lowerlimits of 45 wt %, 25 wt %, 10 wt %, or even 1 wt % or less arecontemplated, depending upon the factors mentioned above. For example,an emulsion may use 0.03 wt %. Examples of applications where lowerconcentrations of HVLCM may be useful include: oil in water emulsion,where the active compound is dissolved or suspended in the HVLCM, whichis then suspended in a continuous phase (e.g., an aqueous phase) as anemulsion; formulations where the HVLCM functions to enhance thesolubility of the active compound in the formulations; and formulationswhere only a slight increase in delayed release is desired.

Example 1

High Viscosity Liquids of DL-Lactide/ε-Caprolactone 75/25 initial MoleConcentration, Reacted with 1,6-Hexanediol.

A clean, one liter glass reaction flask was fitted with a stainlesssteel mechanical stirrer rinsed with acetone, and dried for 3 hoursunder 0.5 mm Hg vacuum, while immersed in a 150° C. oil bath. Thereaction vessel was removed from the bath, allowed to cool, then chargedwith 197.5 grams (1.37 mol) of DL-Lactide, 52.5 grams (0.46 mol) ofε-Caprolactone, and 40 grams (0.34 mol) of 1,6-Hexanediol. Followingaddition, the reaction flask was purged 5 times with nitrogen, andimmersed in the oil bath at 150° C. The mixture was stirred slowly aftera majority appeared to have been melted to facilitate phase change.After all contents had melted, 1.28 mL (210 μmol) of a 0.164M stannous2-ethylhexanoate solution in toluene was added. Stirring continued todisperse the catalyst for a period of approximately 1 hour. The solutionwas maintained, without stirring, for 18 hrs. at 150° C. The resultingcompound was then dried under vacuum (<0.5 mm Hg) at 150° C. or a periodof 4-5 hours to remove any unreacted starting materials, with slow stirspeed applied. The resulting product had an inherent viscosity of 0 049dL/g in CHCl₃ at 30° C.

Example 2

High Viscosity Liquid of DL-Lactide/Glycolide at 75/25 Initial MoleConcentration, Reacted with 1,6-Hexanediol.

The procedure detailed in Example 1 was used to prepare a material using247.13 g (171 mol) DL-Lactide, 62.87 g (0.54 mol) Glycolide, and 49.6 g(0.42 mol) 1,6Hexanediol. Following initial melting, 1.84 mL (260 μmol)of a 0.141M stannous 2-ethylhexanoate solution in toluene was added. Theresulting product had an inherent viscosity of 0.058 dL/g in CHCl₃ at30° C. The material was a liquid at room temperature.

Example 3

High Viscosity Liquid of DL-Lactide/ε-Caprolactone at 75/25 Initial MoleConcentration, Reacted with Glycerol.

The procedure described in Example 1 was used to prepare a materialusing 198.14 g (1.37 mol) DL-Lactide, 54.8 g (0.47 mol) ε-caprolactone,and 40 g (0.43 mmol) Glycerol. Following initial melting, 1.36 mL (210μmol) of a 0.154M stannous 2-ethylhexanoate solution in toluene wasadded. The resulting product had an inherent viscosity of 0.038 dL/g inCHCl₃ at 30° C. The product was a liquid at room temperature.

Example 4

High Viscosity Liquid of DL-Lactide/Glycolide at 7525 Initial MoleConcentration, Reacted with Glycerol.

The procedure described in Example 1 was used to prepare a compoundusing 247.33 g (1.72 mol) DL-Lactide, 62.87 g (0.54 mol) Glycolide, and50.0 g (0.54 mol) Glycerol. Following initial melting, 1.46 mL (260μmol) of a 0.79M stannous 2-ethylhexanoate solution in toluene wasadded. The resulting product had an inherent viscosity of 0.028 dL/g inCHCl₃ at 30° C. The material was a liquid at room temperature.

Example 5

High Viscosity Liquid of Glycolide Reacted with Glycerol

A clean, one liter glass reaction flask was fitted with a stainlesssteel mechanical stirrer rinsed with acetone, and dried for 3 hoursunder 0.5 mm Hg vacuum, while immersed in a 150° C. oil bath. Thereaction vessel was removed from the bath, allowed to cool, then chargedwith 174 grams (1.5 mol) of glycolide and 92 grams (1.0 mol) ofglycerol. Following addition, the reaction flask was purged 5 times withnitrogen, and immersed in the oil bath at 150° C. The mixture wasstirred slowly to facilitate phase change after a majority of themixture appeared to have been melted. After all contents had melted,1.28 mL (210 μmol) of a 0.164M stannous 2-ethylhexanoate solution intoluene was added. Stirring was continued to disperse the catalyst for aperiod of approximately 1 hour. The solution was maintained, withoutstirring, for 18 hrs. at 150° C. The resulting compound was then driedunder vacuum (<0.5 mm Hg) at 150° C. for a period of 4-5 hours with slowstir speed applied to remove any unreacted starting materials.

Example 6

High Viscosity Liquid of ε-Caprolactone Reacted with 1-Dodecanol.

The procedure described in Example 5 was used to prepare a materialusing 513 gms (45 mol) ε-caprolactone and 93 g (0.5 mol) 1-dodecanol.Following addition of reagents, 1.36 mL (210 μmol) of a 0.154M stannous2-ethylhexanoate solution in toluene was added. The reaction proceededas described in Example 5 and was purified as described therein.

Methods of using the compositions of the invention are exemplifiedbelow.

Example A

CAPROL 10G4O (decaglycerol tetraoleate) was dissolved in benzyl benzoateat a weight ratio of 50:50. Bupivacaine was dissolved in this mixture ata concentration of 8.75 wt %. Drops weighing approximately 100 mg wereprecipitated into a test tube containing 40 mL of buffer. Samples of thebuffer were removed at specified time points and replaced with freshbuffer. The samples were analyzed by UV-vis spectrophotometry at 265 mmto determine the concentration of bupivacaine in each buffer sample. At4 hours, less than 7.5 wt % of the bupivacaine in the drop had beenreleased to the buffer. At 48 hours, around 24.0 wt % of the bupivacainehad been released. The cumulative release profile is shown in FIG. 1.

Example B

The 1,6-hexanediol lactate ε-hydroxycaproic acid produced in Example 1was dissolved in N-methylpyrrolidone at a weight ratio of 70:30. 10 wt %bupivacaine base was then added to this mixture and dissolved. Dropsweighing approximately 100 mg were precipitated into 40 mL buffer.Samples of buffer were removed at specified times and replaced withfresh buffer. Buffer samples were analyzed by UV-vis spectrophotometryat 265 nm to determine the concentration of bupivacaine in each buffersample. At 4 hours, around 4.1 wt % of the bupivacaine contained in theprecipitated drop had been released. At 24 hours, around 8.6 wt % of thebupivacaine had been released. The cumulative release profile is shownin FIG. 1.

Example C

The glycerol lactate glycolate prepared according to Example 4 wasdissolved in ethanol at a weight ratio of 70:30. 10 wt % estradiol wasthen added to this mixture as a suspension. The formulation washomogenized prior to testing to ensure adequate mixing. Drops of thisformulation were injected into a test tube containing buffer. Theglycerol lactate glycolate precipitated, forming a depot from which theestradiol was slowly released. Samples of the buffer were removed atspecified times and replaced with fresh buffer. The buffer samplesremoved from each test tube were analyzed by UV-vis spectrophotometry at280 nm to determine the estradiol concentration in each sample. Theassayed concentration was used to calculate the percent of estradiolreleased from the drop. FIG. 2 shows a cumulative release profile forestradiol

Example D

The 1,6-hexanediol lactate glycolate prepared according to Example 2 wasdissolved in propylene carbonate at a weight ratio of 80:20. 10 wt % ofprogesterone was incorporated as a suspension into this mixture. Theformulation was homogenized prior to testing to ensure adequate mixing.The resulting formulation was analyzed to determine its in vitrodissolution profile. Drops of the formulation were injected into a testtube containing buffer. The 1,6-hexanediol lactate glycolateprecipitated, forming a depot from which the progesterone was slowlyreleased. Samples of the buffer were removed at specified times andreplaced with fresh buffer. The buffer samples were analyzed by UV-visspectrophotometry at 244 nm to determine drug concentration in eachsample. The assayed concentration was used to calculate the percentageof progesterone that had been released from the drop. The cumulativerelease profile is shown in FIG. 3.

Example E

The glycerol lactate ε-hydroxycaproic acid prepared according to Example3 was dissolved in polyethylene glycol (PEG) 400 at a weight ratio of36:64. Lysozyme was ground with a mortar and pestle and the resultingpowder was incorporated into the mixture as a suspension at aconcentration of 10 wt %. The formulation was mixed thoroughly with aspatula. Samples of the formulation, approximately 500 μL in volume,were injected into three test tubes each containing 10 mL of buffer.Aliquots of buffer (8 mL) were removed at specified times and replacedwith fresh buffer. Each sample of buffer containing lysozyme wasanalyzed with a micro BCA protein assay reagent kit to determine proteincontent in the dissolution sample. The assayed lysozyme concentrationwas used to calculate the percent of lysozyme that had been releasedfrom the drop. The cumulative release profile is shown in FIG. 4.

Example F

CAPROL 6G2O (hexaglycerol dioleate) was dissolved in benzyl benzoate ata weight ratio of 25:75. Lysozyme was ground with a mortar and pestleand the resulting powder was incorporated into the mixture as asuspension at a concentration of 10 wt %. The formulation was mixedthoroughly with a spatula. Samples of the formulation, approximately 500μL in volume, were injected into three test tubes each containing 10 mLof buffer. Aliquots of buffer (8 mL) were removed at specified times andreplaced with fresh buffer. Each sample of buffer containing lysozymewas analyzed with a micro BCA protein assay reagent kit to determineprotein content in the dissolution sample. The assayed lysozymeconcentration was used to calculate the percent of lysozyme that hadbeen released from the drop. The cumulative release profile is shown inFIG. 4.

Example G

Two solutions were prepared in which 1,6-hexanediol lactateε-hydroxycaproic acid (prepared according to Example 1) and1,6-hexanediol lactate glycolate (prepared according to Example 2) weredissolved in polyethylene glycol (PEG) 400 at weight ratios of 34:66 and33:67, respectively. A drop of each formulation was injected into a testtube containing deionized water, and the 1,6-hexanediol lactateε-hydroxycaproic acid and 1,6-hexanediol lactate glycolate wereprecipitated at the bottom of the test tubes. The drops retained theirshapes for longer than one week.

Example H

The formulations listed in the Table below were prepared using theesters prepared in Examples 1 through 4. In each case, the mixtureresulted in a homogeneous solution.

Ester:Solvent Ester Solvent Wt Ratio 1,6-hexanediol lactate Ethanol80:20 glycolate 1,6-hexanediol lactate ε- Ethanol 80:20 hydroxycaproicacid glycerol lactate ε- Ethanol 80:20 hydroxycaproic acid glycerollactate glycolate Ethanol 80:20 1,6-hexanediol lactate Propylenecarbonate 80:20 glycolate 1,6-hexanediol lactate ε- Propylene carbonate80:20 hydroxycaproic acid glycerol lactate ε- Propylene carbonate 80:20hydroxycaproic acid glycerol lactate glycolate Propylene carbonate 80:201,6-hexanediol lactate Polyethylene glycol 36:64 glycolate (PEG) 4001,6-hexanediol lactate ε- Polyethylene glycol 34:66 hydroxycaproic acid(PEG) 400 glycerol lactate ε- Polyethylene glycol 33:67 hydroxycaproicacid (PEG) 400 glycerol lactate glycolate Polyethylene glycol 37:63(PEG) 400 1,6-hexanediol lactate N-methyl-2-pyrrolidone 80:20 glycolate1,6-hexanediol lactate ε- N-methyl-2-pyrrolidone 80:20 hydroxycaproicacid glycerol lactate ε- N-methyl-2-pyrrolidone 80:20 hydroxycaproicacid glycerol lactate glycolate N-methyl-2-pyrrolidone 80:201,6-hexanediol lactate Benzyl benzoate 70:30 glycolate 1,6-hexanediollactate Glycofurol 70:30 glycolate 1,6-hexanediol lactate Dimethylsulfoxide 70:30 glycolate 1,6-hexanediol lactate ε- Propylene glycol50:50 hydroxycaproic acid 1,6-hexanediol lactate ε- Benzyl benzoate70:30 hydroxycaproic acid 1,6-hexanediol lactate ε- Glycofurol 70:30hydroxycaproic acid 1,6-hexanediol lactate ε- Dimethyl sulfoxide 70:30hydroxycaproic acid glycerol lactate ε- Propylene glycol 50:50hydroxycaproic acid glycerol lactate ε- Benzyl benzoate 70:30hydroxycaproic acid glycerol lactate ε- Glycofurol 70:30 hydroxycaproicacid glycerol lactate ε- Dimethyl sulfoxide 70:30 hydroxycaproic acidglycerol lactate glycolate Propylene glycol 50:50 glycerol lactateglycolate Glycofurol 70:30 glycerol lactate glycolate Dimethyl sulfoxide70:30 glycerol lactate glycolate, Ethanol 70:30 acid end glycerollactate glycolate, Propylene carbonate 70:30 acid end glycerol lactateglycolate, N-methyl-2-pyrrolidone 70:30 acid end glycerol lactateglycolate, Propylene glycol 50:50 acid end glycerol lactate glycolate,Glycofurol 70:30 acid end glycerol lactate glycolate, Dimethyl sulfoxide70:30 acid end

Example I

5.33 g of a 10 wt % solution of bupivacaine in a composition containing70:30 SAIB/NMP, prepared as described in U.S. Pat. No. 5,747,058, wasadded to a aerosol container. 14.32 g of propellant R-34a(1,1,1,2-tetrafluoroethane) was added. The mixture formed a solutionthat was easily sprayed with no bubbling or foaming.

Example J

5.44 g of a 10 wt % solution of bupivacaine in a composition containing70:30 SAIB/NMP, prepared as described in U.S. Pat. No. 5,747,058, wasadded to an aerosol container. 16.55 g. of propellant R-134a(1,1,1,2-tetrafluoroethane) was added. The mixture formed a solutionthat was easily sprayed with no bubbling or foaming.

Example K

0.87 g of bupivacaine base was added to an aerosol container, 8.47 g ofan SAIB/propylene carbonate solution (70:30) containing 2.5 wt % of abiodegradable polymer (65:35 DLPLG) was added to the container. 0.98 gof ethanol was added to help the drag dissolve. Once dissolved,approximately 16 g of propellant R-434a (1,1,1,2-tetrafluoroethane) wasadded. The mixture formed a solution that was easily sprayed with nobubbling or foaming.

Example L

SAIB was dissolved in propellants 134a (1,1,1,2-tetrafluoroethane) and227 (1,1,1,2,3,3,3-heptafluoropropane) at levels of 5 and 10 wt %. Clearsolutions were formed.

Example M

An additional example was conducted to evaluate a novelcontrolled-release system, which uses a high-viscosity compound, sucroseacetate isobutyrate (SAIB), for use in providing sustained release oflysozyme. A small amount of solvent converts SAIB to an easilyinjectable liquid. Once injected, the solvent dissipates forming a highviscosity, biodegradable implant. Release profiles can be altered withdifferent solvents and additives.

Ground lysozyme (10 wt %) was suspended in SAIB/solvent mixturesincluding the solvents ethyl lactate, N-methyl-2-pyrolidone (NMP),MIGLYOL 810, and benzyl benzoate. Three poly (DL-lactide-co-glycolide)polymers with either acid, ester, or PEG end groups were evaluated asadditives. To determine release rates, drops of formulation wereinjected into test tubes with pH 624 buffer and then incubated in ashaker at 37° C. At certain times, aliquots of buffer were removed andreplaced with fresh buffer. Lysozyme concentration in buffer wasdetermined by the BCA protein assay. Protein activity was determinedwith an enzymatic assay measuring cell lysis of a suspension ofMicrococcus lysodeikticus spectrophotometrically. Decrease in absorbanceat 450 nm was recorded as a function of time, which is directly relatedto active lysozyme concentration.

At 6 hours, release ranged from 1.3 wt % for the 70:30 SAIB/NMPformulation (110.3±5.0% activity) to 4.5 wt % for the 40:60 SAIB/ethyllactate formulation (107.6±6.1% activity). The percent released at 7days ranged from 46.7% for 40:60 SAIB/ethyl lactate (88.9±6.8% activity)to 96.4% for 70:30 SAIB/MIGLYOL (107.6±70% activity. Addition of 0.5 wt% of each of the three polymers to an SAIB/NMP formulation did notsignificantly affect the release profile.

These results demonstrate that the SAIB/solvent delivery systemdescribed above is capable of providing sustained release of proteins inan active state, and that the rate of release can be modulated toprovide a range of release profiles.

Example N

An additional example was conducted to evaluate the effects offormulation variables on release of chemotherapeutic agents—paclitaxeland 5-fluorouracil (5-U)—from formulations based on an SAIB deliverysystem. It will be understood from the description above that the SAIBdelivery system uses sucrose acetate isobutyrate (SAIB), afully-esterified, water-insoluble sucrose derivative, as a excipient. Itcan be formulated as a low- to medium-viscosity liquid by the additionof small amounts of solvents such as ethanol, MIGLYOL, ethyl lactate,propylene carbonate, or DMSO, resulting in an easily injectableformulation.

Solutions of SAIB in the appropriate solvent were prepared with andwithout the incorporation of an additive. The active was weighed into atest tube and the SAIB/mixture was added and mixed thoroughly to yield asolution or suspension at the desired drug loading. Single drops of themixture were precipitated into buffer by injection with standardsyringes and needles. Samples were maintained at 37° C. in a shaker,sampled periodically, and analyzed by UV-vis spectrophotometry foractive release. Paclitaxel and 5-FU samples were analyzed at 232 nm and266 nm, respectively.

The effect of drug loading was evaluated for paclitaxel. Drug loadingsof 5, 25, and 50 mg/mL were compared. After 7 days, the cumulativerelease for these three drug loading were 106.4%, 85.9%, and 33.8%,respectively. The effect of surfactant additives was also evaluated, A25 mg/mL paclitaxel formulation and a 10 mg/mL 5-FU formulation, both in85:15 SAIB/EtOH, were made and 5 wt % Cremophor EL was added. Theaddition of this surfactant increased the rate of release or bothformulations. The percent released from the paclitaxel formulationincreased from 56.0% to 77.0% after two days in vitro. Likewise, thepercent released from the 5-FU formulation increased from 80.6% to106.0% after two days. A second surfactant, Pluronic® L101, was added toa 10 mg/mL 5-FU in 85:15 SAIB/EtOH formulation. This surfactant alsoincreased the amount released from 80.6% to 102.0% after two days.

The rate of release of drugs such as paclitaxel and 5-fluorouracil fromthe SAIB delivery system can be modulated by formulation variablesincluding drag loading and surfactant type. Also, the duration ofrelease of these drugs from this system can be varied from a few hoursto several days with the shorter duration seen at the lower drug loadingand with the addition of a surfactant.

Example O

Another example was conducted to evaluate the potential of the SAIBdelivery system to provide extended release following oraladministration of antiretroviral drugs used for treating HIV infections.As indicated above, the SAIB delivery system uses sucrose acetateisobutyrate (SAIB), a fully-esterified, water-insoluble sucrosederivative, as an excipient.

Zidovudine (AZT) and dideoxycytodine (ddC) suspensions were prepared bymixing drag with SAIB/solvent solutions with and without a cellulosiccoexcipient. Approximately 1 g of each formulation was filled into softgelatin capsules, which were heat sealed. Dissolution profiles weredetermined using Apparatus 2, Method B1 (USP XXII) at a paddle speed of50 rpm. Individual gelcaps were placed in separate dissolution vessels,and samples of the buffer in each vessel were obtained at 0.25, 0.5, 1,2, 3, 6, and 24 hours. The samples were analyzed at 266 and 272 nm on aPerkin Elmer Lambda 20 UV-vis spectrophotometer for AZT and ddC drugcontent, respectively.

Release of AZT and ddC can be modulated simply by the use of differentsolvents in the SAIB delivery system. By using a 70:30 SAIB/Migylol® 810combination, the cumulative percent released at 2 hours for an 11.1 wt %AZT formulation was 104.1% and 74.2% for a 0.225 wt % ddC formulation.Comparatively, when an 85:15 SAIB/EtOH combination was used, 71.2% ofthe drug in the AZT formulation had been released and 59.5% of the drugin the ddC formulation. Release can also be modified by altering drugloading. When the active loading of an 85:15 SAIB/EtOH formulation wasdoubled from 11.1 to 22.2 wt %, the cumulative percent released wasincreased from 71.2% to 93.3%. The use of a polymeric additive,cellulose acetate butyrate (CAB), to modulate release was alsoevaluated. For an 11.1 wt % AZT in 85:15 SAIB/EtOH formulation, additionof 0.02 and 0.2 wt % CAB decreased the amount released at 2 hours from71.2% to 25.6% and 7.6%, respectively. For a 0.225 wt % ddC in 85:15SAIB/EtOH formulation, addition of 0.5 and 1. wt % CAB decreased theamount released at 2 hours from 59.5% to 39.4% and 135%, respectively.

These data show that formulations of the SAIB delivery system can bemodified to provide a range of dissolution profiles for AZT and ddC. Byproviding controlled release of these actives, this system can reducethe number of pills needed per day, reduce cost of manufacture, andimprove patient compliance.

Example P

A depot formulation was prepared by suspending 0.83 g of a 3:2 (w/w)solid mixture of cromolyn sodium (disodium cromoglycate) andpolycaprolactone (PCL, Birmingham Polymers, Inc.) in 9.17 g of a 70:30(w/w) mixture of SAIB and benzyl benzoate. The solid cromolyn sodium/PCLmixture was prepared by dissolving 12 g PCL in 100 mL of methylenechloride and mixing 18 g cromolyn sodium into this solution. Thesolution was poured onto TEFLON film, and the methylene chlorideevaporated to a solid film, which was then ground into particles, whichwere then added to the SAIB/benzyl benzoate mixture.

The resulting depot suspension was incubated and assayed to determinethe rate of cromolyn release. The formulation was found to release acumulative total of about 9 mg or 10% of available cromolyn over a35-day period as shown in FIG. 5.

Example Q

Cromolyn sodium (1.5 g) was added to a solution of SAIB:benzyl benzoate(74:26 w/w) containing 5 wt % DL.-polyactide (DL-PL). The final cromolynconcentration was 10 wt %. After mixing thoroughly, 500 mg of theresulting suspension was added to a dissolution buffer (PBS, pH of 7.4with sodium azide). Samples were removed at selected time points andanalyzed to determine the amount of cromolyn sodium released. Thisformulation released cromolyn for approximately ten days, as shown inFIG. 6

Example R

A hollow tube of 65:35 poly(dl-lactide-co-glycolide) containing 5 wt %PEG-1000 as a porosigen is extruded on a Randcastle extruder using astandard tubing dye. The resulting hollow rods, having a diameter of 2.0mm are cut to the desired length of 20 mm and filled with a mixture ofSAIB and fibroblast growth factor (FGF). The rod ends are closed by heatsealing. The rods are assayed for release of FGF by placing them in 40mL of HEPES dissolution buffer at 37° C. without agitation. Afterapproximately 1 hour incubation, 5 mL of buffer solution is removed foranalysis and replaced with fresh buffer. Daily sampling is conducted,and the samples analyzed for FGF content by ELISA. The formulation showsa release lag of 2 days, followed by release of about 3 wt % of theoriginal FGF loading per day for 30 days.

The present invention having been thus described, variations andmodifications thereof as would be apparent to those of skill in the artwill be understood to be within the scope of the appended claims.

1.-45. (canceled)
 46. A composition comprising: sucrose acetateisobutyrate (SAIB); benzyl alcohol; and an anesthetic.
 47. Thecomposition of claim 46, wherein the SAIB is present in an amountranging from about 45 wt % to about 99.5 wt %, relative to the totalweight of the composition.
 48. The composition of claim 46, wherein thebenzyl alcohol is present in an amount ranging from about 10 wt % toabout 30 wt %, relative to the total weight of the composition.
 49. Thecomposition of claim 46, wherein the anesthetic is present in an amountranging from about 5 wt % to about 20 wt %, relative to the total weightof the composition.
 50. The composition of claim 46, wherein: the SAIBis present in an amount ranging from about 45 wt % to about 99.5 wt %,relative to the total weight of the composition; the solvent is presentin an amount ranging from about 10 wt % to about 30 wt %, relative tothe total weight of the composition; and the anesthetic is present in anamount ranging from about 5 wt % to about 20 wt %, relative to the totalweight of the composition.
 51. A method comprising administering thecomposition of claim 46 to an animal in need thereof.
 52. A methodcomprising administering the composition of claim 50 to an animal inneed thereof.
 53. The method of claim 52, wherein the administeringcomprises administering parenterally.
 54. The method of claim 52,wherein the administering comprises administering topically.
 55. Acomposition comprising: sucrose acetate isobutyrate (SAIB); a solvent inwhich the SAIB is soluble; and bupivacaine.
 56. The composition of claim55, wherein the SAIB is present in an amount ranging from about 45 wt %to about 99.5 wt %, relative to the total weight of the composition. 57.The composition of claim 55, wherein the solvent is present in an amountfrom about 10 wt % to about 30 wt %, relative to the total weight of thecomposition.
 58. The composition of claim 55, wherein the bupivacaine ispresent in an amount ranging from about 5 wt % to about 20 wt %,relative to the total weight of the composition.
 59. The composition ofclaim 55, wherein: the SAIB is present in an amount ranging from about45 wt % to about 99.5 wt %, relative to the total weight of thecomposition; the solvent is present in an amount ranging from about 10wt % to about 30 wt %, relative to the total weight of the composition;and the bupivacaine is present in an amount ranging from about 5 wt % toabout 20 wt %, relative to the total weight of the composition.
 60. Amethod comprising administering the composition of claim 55 to an animalin need thereof.
 61. A method comprising administering the compositionof claim 59 to an animal in need thereof.
 62. The method of claim 61,wherein said administering comprises administering parenterally.
 63. Themethod of claim 61, wherein the administering comprises administeringtopically.